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PLoS One. 2017 May 10;12(5):e0177188. doi: 10.1371/journal.pone.0177188. eCollection 2017.

BMP-7 induces apoptosis in human germinal center B cells and is influenced by TGF-β receptor type I ALK5.

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Department of Cancer Immunology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo, Norway.
Center for Cancer Biomedicine, University of Oslo, Oslo, Norway.
Faculty of Medicine, University of Oslo, Oslo, Norway.
Laboratory of Cellular Immunology, Ochsner Clinic Foundation, New Orleans, Louisiana, United States of America.
Transplantation Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Department of Cellular Therapy, the Norwegian Radium Hospital, Oslo, Norway.


Selection and maturation of B cells into plasma cells producing high-affinity antibodies occur in germinal centers (GC). GCs form transiently in secondary lymphoid organs upon antigen challenge, and the GC reaction is a highly regulated process. TGF-β is a potent negative regulator, but the influence of other family members including bone morphogenetic proteins (BMPs) is less known. Studies of human peripheral blood B lymphocytes showed that BMP-6 suppressed plasmablast differentiation, whereas BMP-7 induced apoptosis. Here, we show that human naïve and GC B cells had a strikingly different receptor expression pattern. GC B cells expressed high levels of BMP type I receptor but low levels of type II receptors, whereas naïve B cells had the opposite pattern. Furthermore, GC B cells had elevated levels of downstream signaling components SMAD1 and SMAD5, but reduced levels of the inhibitory SMAD7. Functional assays of GC B cells revealed that BMP-7 suppressed the viability-promoting effect of CD40L and IL-21, but had no effect on CD40L- and IL-21-induced differentiation into plasmablasts. BMP-7-induced apoptosis was counteracted by a selective TGF-β type I receptor (ALK4/5/7) inhibitor, but not by a selective BMP receptor type I inhibitor. Furthermore, overexpression of truncated ALK5 in a B-cell line counteracted BMP-7-induced apoptosis, whereas overexpression of truncated ALK4 had no effect. BMP-7 mRNA and protein was readily detected in tonsillar B cells, indicating a physiological relevance of the study. Altogether, we identified BMP-7 as a negative regulator of GC B-cell survival. The effect was counteracted by truncated ALK5, suggesting greater complexity in regulating BMP-7 signaling than previously believed.

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